Sex hormones are a class of compounds produced by the testicles, ovaries, brain, placenta, and/or adrenal glands, which play a major role in reproduction and sexual identity. One class of sex hormones is the steroidal hormones. Steroidal hormones are typically hydrophobic, having low solubility in aqueous solution, and low bioavailability in vivo.
Progesterone is a C-21 steroidal sex hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. Like other steroids, progesterone consists of four interconnected cyclic hydrocarbons. Progesterone is hydrophobic, having an aqueous solubility of 0.007±0.0 mg/ml. Progesterone is biosynthesized from pregnenolone, a derivative of cholesterol.
Progesterone and its analogues can be used to treat a variety of medical conditions, including acute diseases or disorders, as well as chronic diseases and disorders associated with long-term declines of natural progesterone levels. However, progesterone is poorly absorbed when administered orally. PROMETRIUM®, a commercially available progesterone formulation, is an attempt to overcome the poor oral bioavailability of progesterone (see the package insert for PROMETRIUM®). In PROMETRIUM®, the progesterone is micronized and suspended in an edible oil, such as peanut oil. However, clinical trials involving PROMETRIUM® showed significant interpatient and intrapatient variability. For example, a clinical trial involving postmenopausal women who were administered PROMETRIUM® once a day for five days resulted in the mean pharmacokinetic parameters listed in Table1 (see the package insert for PROMETRIUM®).
TABLE 1Pharmacokinetic Parameters for PROMETRIUM ™PROMETRIUM ™ Capsule Dose(mean +/− standard deviation)Parameter100 mg200 mg300 mgCmax (ng/ml)  17.3 ± 21.9a38.1 ± 37.860.6 ± 72.5Tmax (hrs)1.5 ± 0.82.3 ± 1.41.7 ± 0.6AUC(0-10)43.3 ± 30.8101.2 ± 66.0 175.7 ± 170.3(ng * hr/mL)
The unusually high variability in the Cmax and AUC(0-10) (as evidenced by the large standard deviation) indicates that a significant percentage of patients are overdosed or receive a sub-optimal dose. PROMETRIUM™ is also known to exhibit significant intrapatient variability. Finally, the presence of peanut oil in the formulation excludes patients who are allergic to peanut oil.
Attempts to overcome the solubility problems associated with hydrophobic compounds, particularly steroids, have been described in the literature. For example, WO99/08666 by Glaxo Group, Ltd. describes solutions containing a therapeutically effective amount of an aza steroid and a fatty acid ester of glycerol or propylene glycol. The aza steroid is present in a concentration from 0.0025 to 2.5% by weight of the solution, more preferably from 0.025 to 1.5% by weight of the solution, with a dose of 0.1 to 10 mg. Aza steroids are synthetically derived steroids, not steroidal sex hormones. Further, the concentration of the steroid is very low, i.e., less than 2.5% by weight of the fill.
WO 2005/072686 by Stiefel Laboratories describes orally administrable softgels and fill compositions for use in treating various dermatological conditions. In one embodiment, the softgel capsule contains an internal, non-aqueous liquid phase containing a solution or suspension of a single, hydrophobic pharmacologically active agent effective to treat a dermatological disorder and one or more fatty acids or derivatives thereof, such as omega-3 fatty acids, DHA, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, monounsaturated fatty acids, polyunsaturated fatty acids, saturated fatty acids, trans fatty acids, derivatives thereof, and mixtures thereof. Suitable classes of active agent include steroids. However, the '686 application does not disclose or suggest fill materials containing steroidal sex hormones, such as progesterone dissolved in a fatty acid solvent.
WO 2006/102157 by Ivax Pharmaceuticals S.R.O. describes soft gelatin capsules that encapsulate a water-insoluble active agent dissolved in a crystallization inhibitor. The inhibitor contains at least one monoacylglycerol compound whose acyl group is a fatty acid residue of 6-18 carbons. The concentration of the inhibitor is from 2 to 10% w/w of the fill (page 6, lines 9-12). The '157 application does not disclose or suggest a capsule containing a steroidal sex hormone dissolved in a fatty acid solvent, wherein the concentration of the fatty acid solvent is at least 50% by weight of the fill material.
U.S. Pat. No. 5,645,856 to Lacy, et al., describes a pharmaceutical composition containing progesterone in a carrier system containing a digestible oil and a pharmaceutically acceptable surfactant component for dispersing the oil in vivo. EP 0 750 495 to R.P. Scherer Technologies, Inc. describes a pharmaceutical composition containing a lipophilic surfactant component and a hydrophobic drug dispersed or dissolved in a digestible oil which contains a hydrophilic surfactant, where some or all of the oil is the lipophilic surfactant component. The '856 and '495 patents define “digestible oil” as an oil which is capable of undergoing de-esterification in the presence of pancreatic lipase in vivo under normal physiological conditions. The surfactant component may contain a fatty acid such as oleic acid. The '856 patent describes formulations containing up to 50% by weight of the drug. Although progesterone is included in the list of drugs which may be formulated, the concentration of progesterone in the examples does not exceed about 5% by weight.
WO 97/40823 by R.P. Scherer Ltd. describes the '856 patent to Lacy, et al., as achieving a maximum concentration of progesterone of about 4% which requires either a large dosage capsule or requires the dosage to be split into two capsules. In contrast, the '823 application seeks to address low solubilization of progesterone through pharmaceutical compositions containing a hydrophobic drug, a digestible oil, such as triglycerides or propylene glycol esters of medium chain length (C8-C12) and/or long (C13-C22) fatty acids, and propylene glycol monolaurate; a lipophilic surfactant containing a glyceride of C5 to C10 fatty acid; and a hydrophilic surfactant which is a polyoxyethylene hydrogenated castor oil. The '823 application discloses formulations that preferably do not contain unsaturated components. The '823 application describes progesterone formulations containing up to 6.5% by weight progesterone in solubilized form.
U.S. Pat. No. 4,963,540 to Maxson et al. describes pharmaceutical compositions suitable for oral administration containing micronized progesterone dispersed in an oil vehicle which is high in glycerides of polyunsaturated fatty acids. The fill materials can be used to fill capsules, such as softgel capsules. The capsules contain a dose of progesterone from 50-150 mg, particularly 90-110 mg. The oil vehicle is used in an amount ranging from 1.5-2.5 ml per one gram of progesterone. The fill material in the '540 patent is a dispersion, not a solution.
There exists a need for compositions containing higher concentrations of a sex hormone, such as progesterone, and which exhibit higher oral bioavailability, lower interpatient and intrapatient variability, and do not contain carriers which are unsuitable due to a high prevalence of adverse reactions when ingested.
Therefore, it is an object of the invention to provide compositions containing a sex hormone, such as progesterone, that exhibit: (1) increased oral bioavailability, compared to a formulation containing micronized drug suspended in a carrier; (2) lower interpatient and intrapatient variability compared to a formulation containing micronized drug suspended in a carrier, and (3) higher effective concentrations of the hormone; and methods of making and using thereof.
Additionally, it is an object of the invention to provide compositions which do not contain a carrier known to cause adverse reactions.